The hypothesis that the pancreatic beta cell is a primary site of pathology in human and experimental diabetes, and the knowledge that the beta cell population is affected by genetic background and by diet and responds to toxic and infectious agents, has directed our attention to the need for further study of toxic, viral, autoimmune and spontaneous (? genetic) models of diabetes mellitus. It is recognized that an absolute or relative deficiency of pancreatic/circulating insulin, and/or a diminution in its peripheral effectiveness characterizes most examples of clinical and experimental diabetes. This recognition has directed our attention to the need for further study of factors which control and/or modify beta cell sensitivity to glucose as well as the response of peripheral tissues to circulating insulin. This request is for support of several research projects designed to study the role of toxins, viral agents, autoimmunity and hormonal factors in the pathogenesis of experimental diabetes in mice. Support is also requested for studies of spontaneous diabetic syndromes in an outbred strain of Wistar rats. Support is requested for projects designed to study aspects of changing beta cell sensitivity to glucose, as well as morphologic events responsible for insulin secretion in neoplastic and nonneoplastic beta cells. Finally, support is also requested for morphologic studies of skeletal and cardiac muscle plasma membranes under conditions of spontaneous and induced insulin resistance (hyperinsulinemic obese mice).